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Frequently Asked Questions (FAQs)

Cancer Nanomedicines, NCL Application Process

Cancer-related nanostrategies proposed to the NCL for characterization are ranked according to their projected impact on clinical cancer applications and/or furthering nanotechnology’s compatibility with biological systems. Specific evaluation criteria include, but are not limited to:

Previously demonstrated efficacy in vitro and/or in animal models

Advantages offered by the strategy over existing cancer therapies or diagnostics

Previous physical characterization of the nanomaterial such as purity and stability

The nanostrategy’s manufacturing process and compatibility with scale-up

The material’s inherent toxicity and/or environmental concerns

Plans or approach to transition the strategy to clinical trials such as filing the follow-on IND, IDE or pre-IDE

For detailed information on submitting a proposal for a cancer-related project, please visit here.

For the Phase II application, please expand on the information presented in the White Paper and include any additional data you feel best demonstrates the potential of your strategy. Your Phase II invitation letter will also include a list of questions/comments from the review committee for you to address in your Phase II proposal. Additionally, a completed copy of NCL’s Generic Questionnaire is also requested at the time of submission.

Remember, for oral Phase II presentations, a read-ahead copy of the presentation slides and completed questionnaire is requested one-week in advance.

The NCL is located at the Advance Technology Research Facility (ATRF), 8560 Progress Drive, Frederick, MD 21701. The ATRF is approximately equidistant (~ 50 miles) from any of the three Washington, D.C. – Baltimore area airports [Baltimore Washington International Airport (BWI), Dulles International Airport (IAD), or Ronald Reagan Washington National Airport (DCA)]. From the airport you may either take a cab or rent a car to Frederick. Please keep in mind the time of day you travel. Traveling during rush hour could take two hours or more, depending on traffic, weather, or the airport you’re traveling from (DCA is typically the busiest commute).

White Paper application decisions are sent within 45 days of the application deadline. Phase II application decisions are generally sent within about two weeks after an oral presentation, or one month for a written proposal.

Yes, multiple applications are welcome. Please limit an application to description of a single lead formulation for cancer. If you have multiple formulations undergoing development, you are welcome to submit a separate application for each formulation.

Please do not submit a separate application for characterization of non-lead or precursor formulations. Many times, precursor formulations will be included in the characterization assays of the final lead formulation. Due to limited resources, the NCL does not wish to characterize materials you do not intend to pursue for clinical translation unless scientifically justified.

Yes, you can exceed the word limits of the White Paper application. The outlined word limits within each section are typical of most applications, and are generally sufficient. However, you may increase the word count if you feel the additional information is critical to your application. An unlimited number of figures can be included as an addendum to your application. Please simply cite the figure numbers in your application as appropriate.

Please do not simply send published or unpublished manuscripts in lieu of a completed application, or alter the format of the application. The format of the White Paper application allows the review committee to fairly evaluate all incoming proposals based on the same categories and information.

The Phase II presentation can be in the form of a written proposal, typically 6-10 pages, or an oral presentation, typically 30-45 minutes. Although the NCL has a preference for oral presentations, written proposals are not scored any less favorably. The presentation format allows for a real-time discussion between you and the review committee. Written applications may take longer to reach a decision because of the iterative communication to address remaining reviewer questions or concerns.

For a presentation format Phase II application, you are welcome to visit the NCL for a face‐to‐face meeting with NCL scientists, but it is not required. We can conduct the meeting via webconference. In fact, most NCL Phase II presentations are conducted this way. The NCL typically schedules 6-12 Phase II presentations every quarter. Be sure to schedule your presentation early to get the most available timeslots.

Unfortunately, no. While NCL welcomes anyone who wishes to visit NCL facilities for an in-person presentation of their Phase II application, the applicant is responsible for all costs associated with their travel.

The acceptance rate varies somewhat depending on the number and quality of applications we receive each year. On average, about 50% of White Paper applications are ultimately accepted for characterization.

No. NCL characterization is open to both US and non-US investigators and companies. NCL testing is structured to meet the needs of Investigational New Drug (IND) and Investigational Device Exemption (IDE) applications with the US Food and Drug Administration. Non-US entities are asked to seek eventual regulatory approval in the US, should their products continue to demonstrate promise.

Cancer Nanomedicines, NCL Assay Cascade Characterization

Yes! We view our interaction as a collaboration. Prior to the initiation of a project, the NCL staff and project developers engage in multiple interactions via teleconference, email and face-to-face meetings. Once the project begins, the collaborator receives updates about once per quarter on the physical characterization, immunology and toxicology data generated from the NCL assay cascade.

The NCL and collaborators jointly work through any issues that might arise. For example, it is not uncommon for a nanoparticle formulation to have impurities in the first batches submitted to the NCL. In these situations, NCL staff work with collaborators to identify any contaminants; the NCL may then recommend methods to further purify the preparation.

Required amounts will depend upon the individualized research plan for each project. For a material undergoing physicochemical characterization, in vitro analyses, and in vivo studies, we typically require ½ to 1 gram of your nanomaterial. Depending on the availability of resources during the application process, NCL may be able to assist researchers with scale-up in order to have enough nanomaterial to enter the assay cascade.

No, not every submitted nanoparticle goes through the entire assay cascade. Prior to your submission of material to the NCL, we will have a teleconference to jointly outline an individualized research plan, estimate required material amounts, and prioritize characterization experiments. Factors influencing this plan include the type of nanomaterial (e.g. many of the physicochemical assays are material-specific), the collaborator’s previous characterization of the material, the collaborator’s desired knowledge of the material, and the intended final application of the material.

Every particle does go through the “NCL prescreen”– tests to verify the formulation is free of bacteria, yeast, mold, and endotoxin contamination, as well as physicochemical tests to confirm formulation identity (e.g. dynamic light scattering and zeta potential).

This is entirely dependent upon the individualized research plan for each formulation. Generally speaking, most NCL Assay Cascade collaborations take 6-12 months to complete. The entire assay cascade—physicochemical characterization, in vitro screening, and in vivo studies—can be completed in one to one-and-a-half years. However, many factors may shorten or lengthen this timeframe. Issues with nanomaterial sterility, endotoxin levels, and production of adequate amounts of material can delay the process. NCL has over 20 ongoing collaborations at any time, and we prioritize experiments on a weekly basis based on our characterization demands and results.

Here is a general timeline for NCL characterization:

1-1.5 months

In general, we perform the “NCL prescreen” within 45 days of receiving your nanomaterial. The prescreen consists of tests for contamination (bacterial, yeast, mold and endotoxin), as well as preliminary physicochemical tests for size distribution, such as dynamic light scattering (DLS), and zeta potential.

2-6 months

Once the prescreen is complete, if everything looks good, we continue with expanded physicochemical characterization and in vitro testing. This includes measurement of physicochemical characteristics like drug loading, purity, stability and surface characteristics, as well as evaluation of in vitro blood contact properties (plasma protein binding, hemolysis, platelet aggregation, complement activation, etc.). This phase can be slowed considerably if one of our experiments appears to give spurious results (results not in-line with the results of the other experiments) or if we discover a property of the nanomaterial that was unanticipated (e.g. unexpected toxicity or interference with the assay).

6-12 months

Physicochemical and in vitro characterization continues during this period, adding in vitro evaluation of effects on cell viability and immune cell function using a variety of methods. Finally, if everything continues to look promising, we may begin vivo experiments. We usually start with a dose-range finding toxicity study to determine the toxic dose and target-organs for any toxic response to the nanomaterials. This takes 1-2 months. This is usually followed by a biodistribution study, using available methods to track the distribution and clearance of the nanomaterial, and/or an efficacy study, evaluating the nanomaterial in either a xenograft or transgenic cancer model in rodents. Each of these studies typically takes 2-3 months to plan, conduct, and analyze the results. Finally, we usually conduct the full subacute toxicity study as the final phase of NCL characterization. This study is very involved and may take 4-6 months to complete. It is also the most expensive, and likely the most important for an IND.

Keep in mind that the above timeline assumes everything goes well and that there are no unexpected results – this is uncommon, since there are almost always unexpected results!

Experiments are prioritized on a weekly basis based on our characterization demands and results. NCL continually performs characterization experiments and assesses project needs, beginning from the time a particle is submitted (i.e., particles submitted earlier are generally scheduled first). A minimum subset of characterization data is guaranteed to be performed in the first forty-five days: DLS, zeta potential, sterility, and endotoxin quantification.

That being said, NCL has over 20 ongoing collaborations at any time, which may take priority over your characterization project. We will make every effort to keep you updated on timeline adjustments. NCL is sensitive to the needs of its collaborators and, as possible, will adjust schedules to provide data to meet deadlines such as pre-IND meetings with the FDA.

In short, the NCL examines the weight of the evidence from preclinical studies, looking for “consensus behavior”. A published study1 demonstrated interference of carbon nanotubes with the MTT assay. The study showed that carbon nanotubes have the ability to absorb the formazan dye, giving the appearance of a reduction in cell viability. This phenomenon helped to explain the lack of consensus behavior of carbon nanotubes in the in vitro toxicology literature where groups were using different cytotoxicity endpoints and arriving at contrasting conclusions regarding carbon nanotube cytotoxicity.

Even if the previous toxic responses attributed to carbon nanotubes in vitro were the result of MTT assay interference, this does not mean that carbon nanotubes are necessarily safe, as often in vitro results are not predictive of in vivo responses due to the complexities inherent in the whole organisms (i.e. exposure-dose-response relationships, cell-cell interactions, etc.). As such, it is important to look at the total body of evidence.

The NCL works closely with its collaborators to address any safety/efficacy issues or inconsistencies. Development of a collaborator’s nanotech strategy is an iterative process and the NCL will attempt to offer suggestions as to how to further optimize a sponsor’s nanoparticle. The NCL will then characterize the improved “batch” of nanoparticles.

If the scope of improvements to a nanoparticle’s formulation is drastic, such as a change in the targeting modality, the NCL would require the sponsor to reapply for evaluation. The new material would need to demonstrate efficacy and would require the characterization to start from scratch.

Generally speaking, the NCL would prefer to characterize only one lead nanomaterial -- your most promising candidate formulation for promotion to clinical applications. In addition, the NCL usually requires control nanomaterials and synthetic precursors for experimental comparison. If something unexpected happens and you decide you’re not taking that formulation to clinic, you are welcome to apply for characterization of other formulations, and NCL is happy to apply whatever it learned about the first particle to subsequent formulations. Previous acceptance of one formulation, however, does not automatically guarantee acceptance of a subsequent formulation for NCL characterization.

If you’ve not yet decided on a lead formulation, NCL may be able to help with lead selection. These experiments are generally conducted through a sponsor-funded Collaborative Research and Development Agreements (cCRADA) with Leidos Biomedical Research, Inc.

NCL data is provided to our collaborators via webconference throughout the study period, several times a year, with ample opportunity for discussion of results and development of upcoming experimental plans. When characterization is complete, a fully inclusive report is presented to the collaborator detailing results of all NCL experiments.

Updates on the progress of the nanomaterial characterization project are provided to NCL collaborators at regular intervals – approximately once per quarter–in the form of powerpoint presentations (webconferences), discussions (teleconferences), and simple updates communicated by email. Once characterization of the nanomaterial is complete, a formal report of data from the NCL assay cascade is provided to the collaborator.

FDA Interactions

Once an IND or IDE has been submitted, some optimization or experimentation is usually necessary in response to FDA reviewer comments. NCL, provided it is within our capabilities, can continue to provide characterization assistance to help address FDA concerns.

No. Occasionally, clinical trials can unveil a previously unaddressed concern or reveal previously undetected toxicities. Such results can often lead to the reformulation of a drug developer’s strategy. NCL remains committed to advancing viable nanotechnology-based drug formulations not just to clinical trials, but also to the market. NCL, provided we have the capabilities, can offer further assistance in both formulation advice and characterization assays.

As a formal collaboration between the National Cancer Institute (NCI), the National Institute of Standards and Technology (NIST), and the Food and Drug Administration (FDA), the NCL makes an effort to maintain transparency to its governing institutions. In that spirit, all NCL characterization data are available to the FDA. The NCL and FDA work together on many aspects of nanomaterial characterization, and the FDA is informed about the properties of NCL nanomaterials as data are being generated. Annually, NCL scientists formally present characterization information and data related to NCL nanomaterials to the NCL’s Scientific Oversight Committee, which includes representatives from the FDA.

However, if an NCL sponsor initiates and files an IND with the FDA, the sponsor decides what, if any, NCL data are included in their IND and how the NCL information is presented.

Data derived from the NCL assay cascade are intended to be included in an investigator-led filing of an Investigational New Drug (IND) with the FDA. Since the NCL sponsor initiates and files the IND, the sponsor decides if and how NCL data are presented to the FDA in the IND filing. NCL data alone, however, will not be sufficient to meet the FDA’s requirements for an IND. If the NCL’s assays predict favorable in vivo safety and efficacy, NCI and the NCL anticipate the sponsor will pursue the translation of the technology into clinical applications.

Funding & Costs

If a cancer nanotechnology strategy/material is selected for characterization, NCL’s Assay Cascade services are provided at no cost to the submitting investigator. As part of its assay cascade, the NCL may characterize the nanomaterial’s physical attributes, in vitro biological properties, and in vivo compatibility using animal models.

Non-cancer nanomaterial research projects are individually designed for each interested party; therefore, the costs are highly variable. Some examples are provided here for reference. To discuss your specific non-cancer nanotechnology testing needs and get an estimate of the associated costs, please contact the NCL to schedule a teleconference.

Importantly, the NCL does not profit from agreements such as the Collaborative Research and Development Agreement (cCRADA). NCL is permitted to charge only for actual costs incurred and facility overhead. Any sponsor-paid funds not spent at the end of the project will be returned to the funding partner.

No. The NCL is a resource enabling researchers in academia, industry, and government to transition their nanotechnology strategies to clinical applications. The NCL provides critical infrastructure and characterization services but does not fund research grants.

Intellectual Property & Confidentiality

The NCL takes the same security measures for protection of NCL sponsor intellectual property as for NCL data; every effort is made to ensure security and confidentiality. All confidential/proprietary information disclosed to the NCL is strictly protected and will not be disclosed. To share and safeguard research material and proprietary information, the NCL’s interaction with sponsors is normally conducted under a Material Transfer Agreement (MTA) which includes a non-disclosure clause. The MTA permits the collaborative exchange of materials and data between the NCL and the sponsor. In certain circumstances, NCL–sponsor interaction is conducted under a Cooperative Research and Development Agreement (CRADA), which also contains a non-disclosure clause.

The nanotechnology samples represent significant investments on the part of the laboratories and investigators submitting to the NCL. Many of these samples took years to develop and optimize. The NCL is cognizant of this, and is careful to retain control of the samples. NCL samples are not transferred to anyone not under the direct supervision of the NCL without advance notification to the sponsor. The samples are used only for research purposes, not for commercial purposes such as production or sale. When NCL characterization is complete, the NCL archives a sample of each submitted nanomaterial. Any remaining sample is disposed of or returned to the sponsor.

Publication

Certainly. NCL scientists greatly appreciate the opportunity to collaborate on publications. NCL data are intended to be used in regulatory filings, in publications, and to garner interest from venture capital.

Absolutely not! The NCL does not publish information provided by its sponsors without their express written permission.

In contrast, data generated by the NCL from characterization of a material may be presented in scientific and public forums if such data are deemed to benefit the cancer research community. This public disclosure, however, pertains only to data generated by the NCL; a sponsor company’s proprietary/confidential information is protected and will not be disclosed under any circumstances. Furthermore, the NCL and its sponsors agree to treat in confidence any written information about the research materials that is indicated as confidential.

Unfavorable results and helpful tips on what does not work are an important part of advancing the nanotech field. NCL often receives requests for the “lessons learned” from the field. When appropriate, this data is presented in publication or in workshops. Confidential or proprietary information is always redacted in these public disseminations.

Non-Cancer Nanotechnology

The NCL generally does not accept proposals for Assay Cascade characterization of nanomaterials intended for application in areas other than cancer. We may, however, be able to help via other mechanisms, such as a Collaborative Research and Development Agreements (cCRADA), Collaboration Agreements, or for other Government agencies, via Interagency Agreements with the National Cancer Institute. More information on the types of non-cancer nanotechnology work the NCL performs, please visit here. To discuss your specific non-cancer nanotechnology needs, please contact the NCL to schedule a teleconference.